It is becoming increasingly clear that the tissue microenvironment plays a critical role in regulating inflammation and tissue destruction. Chronic inflammation and tissue fibrosis lead not only to an influx of inflammatory cells/mediators and turnover of the extracellular matrix, but also to increased extracellular concentrations of the purine nucleotide adenosine. Recently fragments of the extracellular matrix component hyaluronan (HA) have been shown to play a central role in the development of lung inflammation and fibrosis in animal models. Similarly, adenosine has been shown to be a crucial negative regulator of inflammation and tissue protector from immune destruction. We posit that the extracellular matrix is both the target of inflammation and a central activator of inflammatory cells and that adenosine is a key modulator of HA-induced inflammation. We hypothesize that within the tissue microenvironment, a critical mechanism by which adenosine exerts its anti-inflammatory effects is by modulating HA fragment induced tissue injury via engagement of the A2a adenosine receptor (A2aR). Interestingly, LMW HA fragments may also augment inflammation by down regulating expression and function of this anti-inflammatory A2aR. Thus the ultimate outcome of tissue inflammation is in part dictated by the interplay between LMW HA fragments and tissue derived adenosine. To this end, in Specific Aim 1, we hypothesize that A2aR ligation modulates HA fragment-induced inflammatory gene expression. We will perform studies in macrophages and airway and alveolar epithelial cells to define the molecular pathway by which adenosine, via A2aR engagement, modulates HA-induced gene expression. In Specific Aim 2, we hypothesize that LMW HA augments inflammation by downregulating the anti-inflammatory A2aR. We will perform studies to define the molecular mechanisms by which LMW HA modulates A2aR expression. Specific Aim 3 hypothesizes that endogenous adenosine modulates bleomycin-induced lung inflammation and fibrosis and that pharmacologic administration of A2aR agonists can protect against disease. We will perform in vivo experiments to demonstrate that bleomycin injury is worse in the absence of A2aR expression. Furthermore, we will define the role of A2aR stimulation on macrophages, and lung airway and alveolar epithelial cells in mediating this protective effect. By defining the pro- and anti-inflammatory properties of extra cellular matrix components, we will be better able to identify specific pharmacologic targets as potential therapies. We believe that these studies will provide the pre-clinical basis for the use of A2aR specific agonists in the treatment of inflammatory lung diseases such as idiopathic pulmonary fibrosis, chronic bronchitis and emphysema.